Type I diabetes (T1D) afflicts 29.1 million people and 9.3% of the United States population. In spite of increased awareness and improved living conditions, and the distribution of similar risk (HLA) genes, T1D has been rising recently at an alarming rate in the world, and especially in the Scandinavian countries, among children. T1D is recognized as an autoimmune disease mediated by T lymphocytes in individuals with genetic predisposition. Despite decades of research, the details of the mechanisms involved in the manifestation of T1D remain sketchy. Many clinical trials have been conducted aiming at the prevention of the onset as well as halt the progression of T1D. These include induction of oral tolerance against insulin, reduced exposure to dietary components such as cow's milk and gluten, blocking the availability of cytokines and other mediators that can potentially cause damage to beta cells using antibodies, and reducing the frequency of autoreactive T lymphocytes by administering antibody against the T cell receptor and other accessory components. However, all of these attempts have met with little or no success for the alleviation of T1D. The failure of these various attempts to intervene the progression of T1D in seropositive individuals is primarily attributed to the poor understanding of the disease process resulting in the inability to pinpoint the time and method of intervention for effective control of T1D.
In addition to the poor understanding of the underlying mechanisms of T1D, the lack of robust diagnostic tests confounds early diagnosis and treatment of this disease. The only available diagnostic test to date is the detection of antibodies against insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma antigen 2 (IA-2A), and zinc transporter 8 (ZNT8A), using expensive and radioactive methods, which are not easily accessible to the general public (Jayaraman (2014) Discov. Med. 17:347-355). HLA genotypes such as HLA DR3/4 are considered to contribute to the susceptibility for developing diabetes. However, these HLA genotypes provide an expected diabetes risk of about 10% in first-degree relatives and therefore are not very reliable in predicting the development of T1D in high-risk individuals. In addition, >50 non-HLA associated regions have been implicated in contributing weak-to-moderate susceptibility to T1D. This was based on determining the single nucleotide polymorphisms (SNPs) in genetic loci revealed by genome-wide association studies (GWAS). However, it is unclear how these SNPs in these loci, each composed of multiple genes, can influence disease outcome. Therefore, these loci do not serve as reliable biomarkers for disease diagnosis or progression. Although these SNPs may indicate the propensity to develop T1D, they cannot be used as biomarkers for the predicting the development of overt diabetes in seropositive individuals (Jayaraman (2014) Discov. Med. 17:347-355).
There are several problems associated with existing antibody detection as a diagnostic test. First, less than 30% of individuals with the genetic predisposition (HLA DR3/4 expression) develop autoantibodies. In addition, occurrence of full-blown diabetes takes a number of years after the appearance of autoantibodies. Further, some individuals, especially Southeast Asians, develop T1D without any sign of autoantibodies. Moreover, it is the T lymphocytes, and not the antibodies, that have been implicated in the destruction of beta cells in T1D. As such, reliability of antibody tests for the diagnosis and prognosis of T1D is questionable.
Recently, a few other biomarkers have been proposed for the detection of T1D, such as differentially expressed genes in the peripheral blood (Bonifacio, et al. (2014) Acta Diabetol. 51:403-11) as determined by microarrays. Whereas the gene expression profiling represents a new line of thinking to find suitable biomarkers for T1D, the selection of genes did not permit the stratification of these patients (Bonifacio, et al. (2014) Acta Diabetol. 51:403-11). Another report necessitated the isolation of subsets of T lymphocytes for microarray analysis (Hisanaga-Oishi, et al. (2014) Endocr. J. 61:577-88). However, this study suffers from a number of shortcomings. Besides being expensive, this analysis is also impractical to perform in a large cohort of patients as a cross-sectional study as well as a longitudinal investigation to correlate the relationship between the expression of certain genes and the onset and/or progression of T1D. Finally, although T1D is considered to be initiated by autoreactive T lymphocytes, recent work has indicated the participation of the innate immune system as well (Jayaraman (2014) Discov. Med. 17:347-355). Therefore, ideal biomarkers should include genes that are over-expressed by T cells as well as the innate immune system under the diabetic condition. Compromised expression of genes implicated in affording protection against diabetes may serve as additional biomarkers for determining the susceptibility to develop diabetes.